PROJECT ABSTRACT Stroke is a leading cause of disability, with an estimated 795,000 cases in the US each year. As many as 70% of patients who suffer a stroke exhibit long-term impairment in upper extremity motor function. The development of rehabilitative strategies to improve the recovery of motor function is of key importance. Neuroplasticity is believed to support recovery after stroke; therefore, manipulations that enhance plasticity may increase recovery. Stimulation of the vagus nerve during motor training drives robust, specific neuroplasticity in rat motor cortex. Recent evidence indicates that vagus nerve stimulation (VNS) delivered during rehabilitative training significantly improves recovery of forelimb function in multiple models of stroke, but the mechanisms underlying VNS-dependent enhancement of recovery are not defined. The cholinergic and noradrenergic neuromodulatory systems are engaged by VNS and represent potential pathways through which VNS may support recovery. We propose to delineate the neuromodulatory pathways and mechanisms by which VNS acts to increase recovery of forelimb motor function after stroke. The first aim of the study will determine whether the cholinergic and noradrenergic systems are required for VNS-dependent enhancement of recovery after stroke. The second aim of the study will evaluate whether direct stimulation of the cholinergic or noradrenergic systems during rehabilitative training is sufficient to enhance recovery. The third aim of the proposal will examine whether anatomical reorganization in descending motor networks is enhanced by VNS therapy to support functional recovery. The results of the proposed experiments will delineate the neuromodulatory pathways and mechanisms by which VNS paired with rehabilitative training enhances recovery after stroke. Insights from these studies will help to determine whether common disease-related and pharmacological factors that influence these neuromodulatory systems may interfere with the beneficial effects of VNS. Ultimately, results from this study will improve the likelihood of successful translation of VNS therapy for stroke patients.